HIV-infected individuals experience up to 4-fold higher annual rates of fragility fractures than the general population. As HIV-infected individuals live longer through effective antiretroviral therapy (ART), fracture rates are expected to further increase in the future. While several studies have emphasized an increased fracture incidence in HIV-infected patients, this increased fracture incidence is not explained by differences in bone mineral density (BMD) between HIV-infected individuals and healthy controls. An emerging explanation for this paradox is that HIV infection and treatment are associated with bone quality changes ? including changes in bone geometry and microstructure ? that do not impact BMD but do increase fracture risk. To date, only a few studies have investigated bone quality and only at the distal extremities. However, the proximal femur is an important site for fragility fracture. Hence, a critical gap in knowledge is whether bone quality at central skeletal sites, including the spine and hip, is similarly affected by HIV infection and therapy. Thus, a critical barrier to progress in the field is a lack of understanding of bone quality changes in HIV infected subjects. A potential mechanism influencing low bone quality in HIV could be an imbalance in bone and fat cell differentiation. Thus, bone marrow fat (BMF) could potentially be another important biomarker for bone health. A better understanding of these relationships could translate into new approaches for fracture risk assessment, drug development, and therapy monitoring in HIV-infected patients. We have identified three working hypotheses: (1) Significant micro-structural deterioration and reduction in biomechanical competence will be detected in HIV-infected patients at both peripheral and central sites and will reveal larger differences between HIV-infected and control groups than BMD data from DXA alone; (2) Increased BMF will be detected in HIV-infected patients compared to healthy controls and will be associated with increased visceral adiposity and decreased HIV-associated subcutaneous adiposity; and (3) Increased BMF will partially explain the association of HIV with poor bone quality. These hypotheses will be tested by pursuing the following Specific Aims: (1) Quantify differences in bone density, structure, and mechanical properties between HIV-infected patients and uninfected controls; (2) Determine differences in BMF between HIV-infected patients and uninfected controls; and (3) Determine the relationship between BMF and bone quality in HIV-infected patients. The approach is innovative because it combines novel in-vivo MRI and HR-pQCT imaging techniques to determine relationships between bone features and BMF with voxel based morphormetry. The proposed research is significant because the associations between bone quality and BMF have not yet been assessed in HIV-infected subjects. These relationships may reveal pathobiological mechanisms at play in HIV, and identify potential therapeutic targets for improving skeletal health in the HIV-infected population.